Nuclear medicine examination enables diagnosis by administrating an agent containing a compound labeled with a specific radioisotope as an effective ingredient (hereinafter referred to as “radiopharmaceutical”) intravenously to a human body and detecting a radiation emitted from the compound, followed by imaging information obtained from the radiation thereof. Nuclear medicine examination is effective in diagnosing a variety of diseases including heart disease and cancer, and characteristic in that it has not only high specificity and sensitivity to diseases, but also an advantage of providing information on the functionality of lesions, compared to other examination techniques.
In addition, radiopharmaceuticals are produced by labeling an unlabeled compound (hereinafter referred to as “labeling precursor”) when necessary, and conducting preparation operations such as purification. Therefore, the labeling precursor is very important as a raw material for synthesizing an effective ingredient, and a method for producing a low-cost and large amount of labeling precursor is requisite for development of radiopharmaceuticals.
Recently, [18F]1-amino-3-fluorocyclobuthanecarboxylic acid (hereinafter referred to as [18F]-FACBC) is researched and developed as a novel radiopharmaceutical. [18F]-FACBC is expected to be developed as a tumor diagnostic agent since it is considered to have a property of being taken up into a cell via an amino acid transporter and largely taken up into tumor cells which are highly proliferative and active in protein synthesis.
It is known that as [18F]-FACBC, there exist compounds different in stereoisomer, which are called syn-form and anti-form (hereinafter referred to as syn-[18F]-FACBC or anti-[18F]-FACBC). Since stereoisomers are usually different in physical and chemical properties, syn-[18F]-FACBC and anti-[18F]-FACBC are defined as different compounds in the development of pharmaceuticals. Therefore, when [18F]-FACBC is used as an effective ingredient of a pharmaceutical, the pharmaceutical must have a composition comprising substantially either one of the stereoisomers.
On the other hand, the method for producing a low-cost and large amount of a labeling compound is important for [18F]-FACBC. Generally, as labeling precursors of radioactive compounds labeled with 18F, compounds in which a leaving group such as triflate is introduced at sites to be labeled are used, and such compounds are usually produced as follows. First, a compound which is substituted by OH group at a position of 18F of a radioactive compound is synthesized. Then, a leaving group such as triflate is introduced to the OH group, and a protecting group is further introduced if necessary. The same synthesis method is disclosed for the labeling precursor of [18F]-FACBC (Patent Document 1).
By the way, for a [18F]-FACBC, inversion occurs in the step of introducing 18F. Therefore, for example, in the synthesis of the labeling precursor used for the synthesis of anti-[18F]-FACBC, a compound in which the OH group is introduced at the syn-position opposite to the 18F position must be synthesized. Similarly, in the synthesis of the labeling precursor used for the synthesis of syn-[18F]-FACBC, a compound in which the OH group is introduced at the anti-position must be synthesized.
For convenience, compounds are hereinafter abbreviated and represented as follows. As required, the term anti- or syn- which indicates a stereoisomer is prefixed, and the case where it is not prefixed means a mixture thereof.
Protected form: an FACBC in which an amino group and a carboxyl group thereof are protected.
OH form: a protected form to which an OH group is introduced at a position to which 18F is to be introduced.
Leaving group adduct: an OH form to which a leaving group is introduced at an OH group thereof.
International Publication No. WO97/017092 pamphlet discloses a method for synthesizing 1-t-butylcarbamate-3-trifluoromethanesulfonoxy-cyclobutane-1-carboxylic acid methyl ester as a labeling precursor of [18F]-FACBC (Patent Document 1).
International Publication No. WO04/056725 pamphlet discloses a method for synthesizing syn-1-t-butoxycarbonylamino-3-[1,2,3,4-tetrafluoro-2-(1,1,2,2-tetrafluoro-2-iodoethoxy)ethanesulfonyloxy]-cyclobutane carboxylic acid methyl ester as a labeling precursor of anti-[18F]-FACBC. This is, as mentioned above, a method of synthesizing a syn-OH form, and then synthesizing a syn-leaving group adduct.    Patent Document 1: International Publication No. WO97/017092 pamphlet    Patent Document 2: International Publication No. WO04/056725 pamphlet